Cardiologists and HbA1c: Novel Diabetes Drugs and the Cardiologist as Diabetician

Transcription

1 Biomarkers 2019 Cardiologists and HbA1c: Novel Diabetes Drugs and the Cardiologist as Diabetician Gregg C. Fonarow, MD, FACC, FAHA, FHFSA Elliot Corday Professor of Cardiovascular Medicine UCLA Division of Cardiology Director, Ahmanson UCLA Cardiomyopathy Center Co-Chief, UCLA Division of Cardiology

2 Diabetes and Cardiovascular Disease Atherosclerotic and HF complications responsible for 80% of mortality among patients with diabetes 75% of all hospitalizations for diabetic complications 50% of patients with type 2 diabetes have preexisting CAD. (This number may be less now that more younger people are diagnosed with diabetes.) 1/3 of patients presenting with myocardial infarction have undiagnosed diabetes mellitus 45% of patients hospitalized with HF have DM Lewis GF. Can J Cardiol. 1995;11(suppl C):24C-28C Norhammar A, et.al. Lancet 2002;359;

3 Diabetes and Survival 50-year-old with diabetes died, on average, 6 years earlier than those without diabetes (58% attributable to vascular, 9%, cancer, 30% other causes ) Reduction in life expectancy from long-term cigarette smoking ~10 years The Emerging Risk Factors Collaboration N Engl J Med 2011;364:829-41

4 Framingham Heart Study 30-Year Follow-up of CVD Events in Patients With Diabetes (Ages 35 64) 10 8 Men Women Risk Ratio Total CVD CHD Cardiac Failure Intermittent Claudication Stroke P<.001 for all values except *P<.05. Wilson PWF, Kannel WB. In: Ruderman N et al, eds. Hyperglycemia, Diabetes and Vascular Disease Kannel WB et al. Am J Cardiol 1974; 34:29-34

5 Diabetes and Heart Failure The two diseases entities are highly co-prevalent Diabetes contributes to disease progression in HF and is associated with substantially worse prognosis, even when conventional HF therapies are applied The relationship between HbA1c and outcome in patients with diabetes and heart failure is complex The choice of pharmacologic glycemic management can markedly impact heart failure outcomes Certain therapies are neutral or associated with harm Certain therapies markedly improve outcomes Pharmacologic glycemic management is a critical component of HF management

6 Diabetes and Incident Heart Failure in the US Framingham study (risk of HF in diabetics) 2x diabetic males 5x diabetic females 4x young diabetic males 8x young diabetic females US HMO prevalence study With diabetes, incident HF developed at a rate of 3.3% per year Each 1% elevation in HbA 1c leads to a 15% increase in frequency of HF Kannel WB et al. JAMA. 1979;241: Nichols GA. Diabetologia. 2000;43(suppl A2):7. Chue CU et al. Circulation. 1998;98(suppl 1):721.

7 Prevalence of Diabetes in Patients with Heart Failure Clinical Trial Diabetics SOLVD 25.8% MERIT 24.5% Val HEFT 25.4% EMPHASIS-HF 31.4% PARADIGM-HF 34.7% OPTIME (hospitalized) 44.2% VMAC (hospitalized) 47.0%

8 Poor Glycemic Control in DM is Independently Associated with Increased HF Risk 10 n=48,858 men and women with Type II DM CHF Rate /year per p< < >10 Hemoglobin A 1c (percent) Iribarren et al. Circulation 2001;103:

9 Heart Failure Rates in Diabetes Glucose Control Trials Risk of HF events with glucose-lowering drugs or strategies versus standard care PPAR Agonists DPP-4 Inhibitors Intensive Control Insulin Weight loss Lancet Diabetes Endocrinol 2015 March 17,

10 Effect of Glycemic Control in Type 2 DM on Cardiovascular Outcomes

11 Diabetics and Heart Failure: Poor Prognosis N = 151,738 Medicare beneficiaries with diabetes, age 65 years N = 5491 patients hospitalized with HF and followed for a median of 7.1 years HR 10.6, 95% CI Multivariate analysis RR DM = 1.5 Bertoni et al. Diabetes Care 27: , 2004 Gustafsson et al. JACC 2003; 43:

12 Major CV Outcome Trials in Type 2 Diabetes SAVOR- TIMI 53 (n = 16,492) 1222 MACE3 CAROLINA N = 6041 MACE4 Omarigliptin (n = 4000) Q42017? MACE4 : DPP4i : SGLT2i : GLP1 EXAMINE (n = 5380) 621 MACE3 TECOS (n = 14,723) 1400 MACE4 CARMELINA N = 8300 MACE *lixisenatide (Sanofi, post-acs). liraglutide (Novo Nordisk). semaglutide (Novo Nordisk). exenatide (Amylin). once-weekly DPP4i (Merck). #dulaglutide (Eli Lilly). ELIXA* (n = 6000) 805 MACE4 LEADER (n = 9341) 611 MACE3 EMPA-REG OUTCOME N = 7034 MACE3 SUSTAIN-6 (n = 3260) MACE3 EXSCEL (n = 14000) MACE3 CANVAS-R (n = 5700) Alb.uria CANVAS (n = 4339) MACE3 FREEDOM (n = 4000)? MACE4 REWIND# (n = 9622) MACE3 DECLARE-TIMI 58 (n = 27,000) MACE3 Ertugliflozin CVOT (n = 3900) MACE3 CREDENCE (n = 3627) Cardiorenal

13 Glycemic Management Medications: Possible Mechansims Impacting CVD and HF

14 SAVOR TIMI 53-Hospitalization for Heart Failure: DPP-4 Time to the 1 st occurrence of any hospitalization for heart failure; 517 events 4% Saxagliptin Placebo HR 1.27 P= % Hospitalization for Heart Failure (%) 3% 2% 1% 0% HR 1.80 P= % 0.6% Scirica BM, et al. Circulation 2014; 130: HR 1.46 P= % 1.3% 2.8% Days from Randomization

15 Hospitalization for HF with Alogliptin: Observations from EXAMINE P interaction =0.068 HR: % CI: P-value: p=0.22 p=0.99 p=0.026 Zannad F. et al. Lancet 2015: 385 :

16 CV Effects of Lixisenatide: ELIXA Trial Results LEADER: Hospitalization for heart failure Pfeffer, M. A., et al. N Engl J Med : Marso SP et al. N Engl J Med. 2016;375:

17 N=3297 T2DM w/ CVD/CV risk Semaglutide 0.5 or 1.0mg vs. placebo once weekly 104 Weeks Outcome # of events HR 95%CI semaglutide vs placebo CV Death/MI/Stroke 108 vs HF hospitalization 59 vs Marso SP, et al. NEJM 2016; DOI: /NEJMoa

18 Liraglutide in Systolic Heart Failure: The FIGHT Trial N=300: liraglutide (n = 154) vs. placebo (n = 146) Margulies KB et al. JAMA. 2016;316:

19 SGLT2 Inhibitors Virtually all glucose filtered by the kidney is reclaimed in the proximal tubule. 1 Sodium glucose cotransporter 2 (SGLT2) is responsible for 90% of this reabsorption. Selective inhibitors of SGLT2 have been developed. 2 By reducing renal glucose reabsorption, SGLT2 inhibitors increases urinary glucose excretion. 3 In patients with type 2 DM, SGLT2 inhibitors leads to: 4 Significant reductions in HbA1c Weight loss Reductions in BP without increases in heart rate 1. Abdul-Ghani et al. Curr Diab Rep. 2012;12: Grempler et al. Diabetes Obes Metab.2012 ;14: Heise T et al. Diabetes Obes Metab 2013;15: Liakos A et al. Diabetes Obes Metab 2014;16:

20 Renal Glucose Re-absorption in Healthy Individuals Filtered glucose load 180 g/day SGLT2 ~ 90% SGLT1 ~ 10% Gerich JE. Diabet Med. 2010;27:

21 Renal Glucose Re-absorption in Patients with Hyperglycaemia Filtered glucose load > 180 g/day SGLT2 ~ 90% SGLT1 ~ 10% When blood glucose increases above the renal threshold (~ 10 mmol/l or 180 mg/dl), the capacity of the transporters is exceeded, resulting in urinary glucose excretion Gerich JE. Diabet Med. 2010;27:

22 Urinary Glucose Excretion via SGLT2 Inhibition Filtered glucose load > 180 g/day SGLT2 inhibitor SGLT1 SGLT2 inhibitors reduce glucose re-absorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis *Loss of ~ 80 g of glucose/day (~ 240 cal/day). Gerich JE. Diabet Med. 2010;27:

23 Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes SGLT2 GLUT2 AMG Uptake 8 P< P<0.05 Normalized Glucose Transporter Levels P< CPM 0 NGT T2DM NGT T2DM NGT T2DM 0 AMG=methyl-α-D-[U 14 C]-glucopyranoside; CPM=counts per minute. Rahmoune H, et al. Diabetes. 2005;54:

24 Mechanism of Action of SGLT2 Inhibitors Inhibition of SGLT2 Reversal of glucotoxicity Insulin sensitivity in muscle GLUT4 translocation Insulin signaling Other Insulin sensitivity in liver Glucose- 6-phosphatase Gluconeogenesis Decreased Cori cycle PEP carboxykinase β-cell function

25 EMPA-REG OUTCOME Trial design: SGLT2 Inhibitor Placebo (n=2333) Screening (n=11531) Randomized and treated (n=7020) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Key inclusion criteria: Adults with type 2 diabetes and established CVD BMI 45 kg/m 2 ; HbA1c 7 10%; egfr 30 ml/min/1.73m 2 (MDRD) 10.2% of patients enrolled with pre-existing heart failure Zinman B et al. N Engl J Med 2015 [Epub ahead of print].

26 EMPA-REG OUTCOME Trial

27 EMPA-REG OUTCOME Study HF Hospitalization or CV Death HF Hospitalization or HF Death Empagliflozin is a highly selective inhibitor of Sodium-Glucose Cotransporter-2 Zinman B et al. N Engl J Med 2015 [Epub ahead of print] adults with type 2 diabetes and established CVD BMI 45 kg/m 2 ; HbA1c 7 10%; egfr 30 ml/min/1.73m 2 (MDRD)

28 Heart Failure Hospitalization or CV death Cumulative incidence function. CV, cardiovascular; HR, hazard ratio; CI, confidence interval. European Heart Journal doi: /eurheartj/ehv728 28

29 European Heart Journal doi: /eurheartj/ehv728

30

31 Heart Failure Hospitalization or CV Death in Patients with vs without HF at Baseline 25 HR 0.63 (95% CI 0.51, 0.78) HR 0.72 (95% CI 0.50, 1.04) Patients with 15 heart failure hospitalization or 10 CV death (%) Patients without heart failure at baseline Patients with heart failure at baseline Zinman B et al. N Engl J Med 2015 [Epub ahead of print].

32 SGLT2 Inhibitors Empagliflozin 1 Dapagliflozin 2 Canagliflozin 3 Launch year 2014(EU/US) 2012 (EU) 2014 (US) 2013 (EU/US) MoA Molecular class Metabolism C-glycoside C-glycoside C-glycoside Dual renal and hepatic 50:50 Mainly hepatic 97:3 Mainly hepatic, no details reported Dosing Administration Oral Oral Oral Regimen Once daily Once daily Once daily Doses 10 mg and 25 mg 5 mg and 10 mg 100 mg and 300 mg

33 Canagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVAS DOI: /NEJMoa

34 CANVAS Program Hospitalization for Heart Failure HR 0.67 (95% CI 0.52, 0.87) ARR=1.6% at 5 y; NNT3y=105; NNT5y=63 33% RRR NNT = 63 Placebo Canagliflozin Number of participants Placebo Canagliflozin Neal B et al. N Engl J Med Jun 12. doi: /NEJMoa

35 Canagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVAS DOI: /NEJMoa

36 Component Analyses of MACE Events: Dapagliflozin S/ENDOCRINOLOGICANDMETABOLICDRUGSADVISORYCOMMITTEE/UCM Pdf

37 Potential Mechanisms Involved in the Reduction of Cardiovascular Events

38 The Metabolodiuretic Promise of SGLT2 Inhibition JAMA Cardiol. 2017;2(9):

39 How Does Empagliflozin Reduce Cardiovascular Mortality? Mediation Analysis of the EMPA-REG OUTCOME Trial In this exploratory investigation into potential mediators of the reduction in risk of CV death with empagliflozin versus placebo, found that changes in hematocrit and hemoglobin, markers of the effects of the drug on volume, appeared to be important mediators of the reduction in mortality risk in univariable and multivariable models. Obesity, blood pressure, lipids, and renal function made negligible contribution Diabetes Care 2018;41:

40 CV Outcome Trials with SGLT2 Inhibitors

41 Upcoming Trials of SGLT2 Inhibitors in HF EMPEROR- Preserved 1 EMPEROR- Reduced 2 Dapa-HF 3 Sample size * 4500 Key inclusion criteria Primary endpoint Key secondary endpoints Start date Expected completion date Patients with chronic HF Elevated NT-proBNP egfr 20 ml/min/1.73 m 2 Symptomatic HFrEF Elevated NT-proBNP egfr 30 ml/min/1.73 m 2 HFpEF (LVEF >40%) HFrEF (LVEF 40%) HFrEF (LVEF 40%) Time to first event of adjudicated CV death or adjudicated HHF Individual components of primary endpoint All-cause mortality All-cause hospitalisation Time to first occurrence of sustained reduction of egfr Change from baseline in KCCQ March 2017 June 2020 March 2017 June 2020 Time to first occurrence of CV death, HHF or urgent HF visit Total number of HHF or CV death All-cause mortality Composite of 50% sustained egfr decline ESRD or renal death Change from baseline in KCCQ February 2017 December 2019

42 SGLT2 Inhibitors, GLP 1 Agonists, and DPP 4 Inhibitors and Outcomes in Patients With Type 2 Diabetes: Meta-Analysis JAMA. 2018;319(15): doi: /jama

43 Comparison of Mortality Reduction in HF Trials with EMPA-REG Trial in Patients with Diabetes European Journal of Heart Failure (2017) 19, 43 53

44 2016 ESC Guidelines for the Diagnosis and Treatment of Acute & Chronic HF European Heart Journal (2016) 37,

45 Conclusions Until 2015, no known diabetes therapy demonstrated in RTCs to improve CV outcomes in general or for HF Most diabetes medications were neutral in ASCVD and worsened outcomes in HF or at best were neutral EMPA-REG Outcome and CANVAS trial data SGLT2 inhibitors are a new option to reduce CV events, CV death and HF in patients with diabetes with and without HF Compelling data Pharmacological diabetes management is an essential component of ASCVD and HF therapy It is critical for cardiologists and HF specialists to play an active role in this management as choice of therapy is key determinate of outcomes, including survival